Design and synthesis of isoxazoline derivatives as factor Xa inhibitors. 2.

Basic Information

ID: ALA1132652

Journal: J Med Chem

Title: Design and synthesis of isoxazoline derivatives as factor Xa inhibitors. 2.

Authors: Quan ML, Ellis CD, Liauw AY, Alexander RS, Knabb RM, Lam G, Wright MR, Wong PC, Wexler RR.

Abstract: Intravascular clot formation is an important factor in a number of cardiovascular diseases. Therefore, the prevention of blood coagulation has become a major target for new therapeutic agents. One attractive approach is the inhibition of factor Xa (FXa), the enzyme directly responsible for thrombin activation. Herein we report a series of isoxazoline derivatives which are potent FXa inhibitors. Optimization of the side chain at the quaternary position of the isoxazoline ring led to SK549 which showed subnanomolar FXa potency (K(i) 0.52 nM). SK549 shows good selectivity for FXa compared to thrombin and trypsin, potent antithrombotic effect in the rabbit arterio-venous thrombosis model, and improved pharmacokinetics relative to other compounds evaluated from this series.

CiteXplore: 10425087

DOI: 10.1021/jm980406a

Patent ID: